Without limiting the scope of the invention, its background is described in connection with antiviral agents.
Influenza A viruses cause a highly contagious respiratory disease in humans that results in a significant loss of life each year, and are responsible for human pandemics that have resulted in higher mortality rates (2). Three pandemics occurred in the twentieth century, in 1918, 1957 and 1968 (23). The 1918 pandemic (“Spanish flu”) was the most devastating, causing at least 20-40 million deaths worldwide (19). H5N1 avian influenza A viruses, which have a human mortality rate of approximately 50% since 1997 (22), are prime candidates for the next pandemic influenza A virus. At present, H5N1 viruses are not readily transmissible between humans, but it is quite possible that they can acquire such transmissability via mutations and/or reassortment of genes with circulating human influenza A viruses.
The primary way of controlling influenza virus epidemics is vaccination, but antivirals provide an important additional line of defense, particularly for a rapidly-spreading pandemic (5, 11). Only two classes of influenza virus antivirals are currently available: inhibitors of the viral M2 ion channel protein (amantadine and rimantadine); and inhibitors of the viral neuraminidase (zanamivir and oseltamivir) (reviewed in 23). The emergence of influenza A viruses resistant to the M2 inhibitors occurs at high frequency in treated patients (4, 21). Many of the human isolates of H5N1 viruses are already resistant to these inhibitors (17). In addition, a recent study has shown influenza A viruses resistant to the neuraminidase inhibitor oseltamivir occurred in 20% of the children treated with this drug (8). In fact, H5N1 viruses that are partially resistant to oseltamivir have recently been reported (9). The emergence of influenza A viruses resistant to these two classes of antiviral drugs highlights the need for additional antiviral drugs against influenza A virus. Therefore, a need exists for novel antiviral agents that address one or more locations in the viral replication cycle.